Is AGPS p.Arg419Cys (c.1255C>T) pathogenic?

AGPS p.Arg419Cys (c.1255C>T) is classified Uncertain significance in AGPS (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-15). AlphaMissense: likely pathogenic (0.9905); Very rare (popmax 0.00446%, eas); Associated with Inborn genetic diseases.

What condition is associated with AGPS p.Arg419Cys (c.1255C>T)?

AGPS p.Arg419Cys (c.1255C>T) is associated with Inborn genetic diseases (ClinVar).

How common is AGPS p.Arg419Cys (c.1255C>T) in the general population?

AGPS p.Arg419Cys (c.1255C>T) is very rare (popmax 0.00446%, eas) (gnomAD).

What do computational predictors say about AGPS p.Arg419Cys (c.1255C>T)?

AlphaMissense predicts likely pathogenic (score 0.9905) — an in-silico prediction, not a clinical call.

AGPS p.Arg419Cys

c.1255C>T · VCV4024842

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9905 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9905	likely pathogenic · top 9% in AGPS
REVEL	0.774	moderately pathogenic-leaning
SaProt	LLR -15.56	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 1.5, phastCons 1
Regional constraint	o/e 0.59	unconstrained · MANE · 145 kb · p 9.9e-28 · regional, not allelic
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00446% East Asian · 2/44,870 alleles

Filtering AF 0.000739% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000276%

Overall 0.00031% 5/1,613,158 alleles · very rare exomes 5/1,461,190 · genomes 0/151,968 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00446%	22,435
Remaining individualsnot grpmax-eligible	0.0016%	62,474
European (non-Finnish)	0.00017%	589,790

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: AGPS
Protein: p.Arg419Cys
Coding: c.1255C>T
MANE Select: NM_003659
Type: single nucleotide variant
Location: chr2:177493169 (GRCh38)
Gene constraint: LOEUF 0.408 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 89.27
Residue 419: a functional site (important for enzyme activity); a UniProt-annotated variant site (in rcdp3; loss of enzyme activity)

Full AGPS gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

AGPS p.Arg419His Likely pathogenic ★ same residue
AGPS p.Arg265Gln Uncertain significance ★★ ⚠ same condition
AGPS p.Asn649Ser Uncertain significance ★★ ⚠ same condition
AGPS p.Asp590His Uncertain significance ★★ ⚠ same condition
AGPS p.Gly9Ala Uncertain significance ★★ ⚠ same condition
AGPS p.Leu120Val Uncertain significance ★★ ⚠ same condition
AGPS p.Phe450Leu Uncertain significance ★★ ⚠ same condition
AGPS p.Pro415Leu Uncertain significance ★★ ⚠ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/agps-p-arg419cys (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown